Inhibition of pro-inflammatory cytokine generation by CTLA4-Ig in the skin and colon of mice adoptively transplanted with CD45RBhi CD4+ T cells correlates with suppression of psoriasis and colitis

Davenport, Colleen; McAdams, Holly A.; Kou, Jen P.; Mascioli, Kirsten; Eichman, Christopher; Healy, Laura L.; Peterson, John J.; Murphy, Sreekant; Coppola, Domenico; Truneh, Alemseged

doi:10.1016/s1567-5769(01)00201-6

Cited by 27 publications

(17 citation statements)

References 43 publications

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“…CTLA4-Ig has shown therapeutic efficacy in several autoimmune diseases including rheumatoid arthritis, and in experimental models of autoimmune diseases [34, 35]. We found that CTLA4-Ig completely prevented colitis and very efficiently cured established disease, indicating a central role of T-cell costimulation in the model.…”

Section: Discussionmentioning

confidence: 63%

Pharmacological Evaluation of the SCID T Cell Transfer Model of Colitis: As a Model of Crohn's Disease

Holm

Poulsen

Markholst

et al. 2012

International Journal of Inflammation

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Animal models are important tools in the development of new drug candidates against the inflammatory bowel diseases (IBDs) Crohn's disease and ulcerative colitis. In order to increase the translational value of these models, it is important to increase knowledge relating to standard drugs. Using the SCID adoptive transfer colitis model, we have evaluated the effect of currently used IBD drugs and IBD drug candidates, that is, anti-TNF-α, TNFR-Fc, anti-IL-12p40, anti-IL-6, CTLA4-Ig, anti-α4β7 integrin, enrofloxacin/metronidazole, and cyclosporine. We found that anti-TNF-α, antibiotics, anti-IL-12p40, anti-α4β7 integrin, CTLA4-Ig, and anti-IL-6 effectively prevented onset of colitis, whereas TNFR-Fc and cyclosporine did not. In intervention studies, antibiotics, anti-IL-12p40, and CTLA4-Ig induced remission, whereas the other compounds did not. The data suggest that the adoptive transfer model and the inflammatory bowel diseases have some main inflammatory pathways in common. The finding that some well-established IBD therapeutics do not have any effect in the model highlights important differences between the experimental model and the human disease.

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Section: Discussionmentioning

confidence: 63%

Pharmacological Evaluation of the SCID T Cell Transfer Model of Colitis: As a Model of Crohn's Disease

Holm

Poulsen

Markholst

et al. 2012

International Journal of Inflammation

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“…21,57,58 While CTLA4-Ig, 59 anti-IFN-␥ monoclonal antibody, 60 and rIL-10 61 have been shown by others to prevent disease progression in this model, no significant efficacy was consistently observed with small-molecule drugs, including cyclosporine A 59 and prednisolone (J.C., Y. Wada, unpublished data, 2001). STA-5326 markedly reduced the inflammatory changes compared with the vehicle control.…”

Section: Discussionmentioning

confidence: 92%

Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor

Wada

Zhou

et al. 2006

Blood

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IntroductionAn array of chronic inflammatory diseases, including Crohn disease, psoriasis, rheumatoid arthritis, and multiple sclerosis, cause widespread and severe health problems. These and other immune diseases can be considered to have a predominantly T helper cell type 1 (Th1) bias. Although injectable biologic treatments such as antibodies and soluble protein that block TNF-␣ have provided significant clinical benefit, there is still a high unmet medical need, particularly for a safe targeted drug that can be taken orally.Interleukin-12 (IL-12) is a heterodimeric cytokine (p70) composed of 2 independently regulated protein subunits, p35 and p40. IL-12 plays a central role in the immune response by bridging innate resistance and antigen-specific adaptive immunity. 1 It is produced from phagocytic cells and antigen-presenting cells, in particular macrophages and dendritic cells, upon stimulation with bacteria, bacterial products such as lipopolysaccharide (LPS), and intracellular parasites. 2,3 The well-documented biologic functions of IL-12 are the induction of interferon-␥ (IFN-␥) expression from T and natural killer (NK) cells 4,5 and the differentiation of naive T cells toward a Th1-cell type. 6,7 IL-12 also appears to be critical in the expansion and maintenance of the Th1 phenotype. [8][9][10] IL-23, a more recently discovered member of the IL-12 family, also promotes Th1 response, but has distinct functions from IL-12. IL-23 is required for the generation of effector memory T cells. 11 IL-23 is also needed for the generation of IL-17-producing T cells, which play a significant role in the inflammatory response. 12 Through these activities, IL-23 plays a critical role in chronic inflammatory diseases.Although the inflammatory effector function of Th1 is essential for the clearance of intracellular pathogens, the excessive production of proinflammatory cytokines leads to serious tissue damage typical of organ-specific autoimmunity, 13,14 including type 1 diabetes, 15 multiple sclerosis, 16,17 rheumatoid arthritis, 18,19 inflammatory bowel disease, 20 psoriasis, 21 and sepsis. 22 IL-12/IL-23 has been validated as an attractive clinical target by a number of studies. Mice lacking the gene encoding the p40 subunit shared by IL-12 and IL-23 or lacking the IL-23-specific subunit p19 have proven the integral role of IL-12/IL-23 to the pathogenesis of these disorders, implying that blockade of the cytokines could be effective in the treatment of a variety of autoimmune diseases. 21,[23][24][25][26][27][28] Monoclonal antibodies to the IL-12/23 p40 subunit have been shown to be effective in human clinical trials in patients with Crohn disease and psoriasis. 29,30 While antibodies against IL-12/IL-23 could provide significant medical benefit, a small-molecule IL-12/IL-23 inhibitor that could be administered orally would be highly desirable. Although some compounds weakly or nonselectively inhibit IL-12, there are no potent and selective small-molecule IL-12 inhibitors. To find an effective inhibitor against the...

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“…Adoptive transfer of Nlrp12 −/− CD4 + CD45RB hi T cells into Rag1 −/− mice also provoked the development of atopic dermatitis in recipient mice ( Figure 5E ), and this was associated with more severe skin pathology ( Figure 5F ). Cutaneous inflammation in this model is typically associated with dysregulated T helper-2 (Th2) cell-associated inflammation(Davenport et al, 2002; Leon et al, 2006; Schon et al, 1997), suggesting that altered IL-4 production may also be contributing to disease pathology.…”

Section: Resultsmentioning

confidence: 99%

The NLRP12 Sensor Negatively Regulates Autoinflammatory Disease by Modulating Interleukin-4 Production in T Cells

et al. 2015

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SUMMARY Missense mutations in the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing family of gene 12 (Nlrp12) are associated with periodic fever syndromes and atopic dermatitis in humans. Here, we have demonstrated a crucial role for NLRP12 in negatively regulating pathogenic T cell responses. Nlrp12−/− mice responded to antigen immunization with hyperinflammatory T cell responses. Furthermore, transfer of CD4+CD45RBhi Nlrp12−/− T cells into immunodeficient mice led to more severe colitis and atopic dermatitis. NLRP12-deficiency did not, however, cause exacerbated ascending paralysis during experimental autoimmune encephalomyelitis (EAE), instead Nlrp12−/− mice developed atypical neuroinflammatory symptoms that were characterized by ataxia and loss of balance. Enhanced T cell-mediated interleukin-4 (IL-4) production promotes the development of atypical EAE disease in Nlrp12−/− mice. These results define an unexpected role for NLRP12 as an intrinsic negative regulator of T cell-mediated immunity, and identify altered NF-κB regulation and IL-4 production as key mediators of NLRP12-associated disease.

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Inhibition of pro-inflammatory cytokine generation by CTLA4-Ig in the skin and colon of mice adoptively transplanted with CD45RBhi CD4+ T cells correlates with suppression of psoriasis and colitis

Cited by 27 publications

References 43 publications

Pharmacological Evaluation of the SCID T Cell Transfer Model of Colitis: As a Model of Crohn's Disease

Pharmacological Evaluation of the SCID T Cell Transfer Model of Colitis: As a Model of Crohn's Disease

Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor

The NLRP12 Sensor Negatively Regulates Autoinflammatory Disease by Modulating Interleukin-4 Production in T Cells

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